The response of intrinsic brain cells to virus infection in the central nervous system (CNS) can influence virus infection in the brain and the clinical outcome of disease. Our studies have focused on two animal models of virus-mediated neuropathogenesis to determine the host response proteins that regulate disease induction. We have identified several host response proteins that are upregulated in the CNS following neurovirulent retrovirus infection or bunyavirus infection and may influence neuronal damage. In FY12, we studied the response of neurons to bunyavirus infection both in vivo and in vitro and identified at least one pathway of innate-immune induced neuronal death during bunyavirus infection. We also further examined how neuropeptide Y (NPY), a molecule that we showed to produced by neurons in response to retroviral infection in the CNS, influenced retroviral pathogenesis. Our current studies demonstrate that administration of NPY can slow the progression of neurological disease following retorviral insult to the CNS. We also identified a difference in the recruitment of macrophages to the CNS in wildtype and NPY deficient mice following retrovirus infection.